Recent Advances in the Synthesis of β-Carboline Alkaloids

Abstract

β-Carboline alkaloids are a remarkable family of natural and synthetic indole-containing heterocyclic compounds and they are widely distributed in nature. Recently, these alkaloids have been in the focus of interest, thanks to their diverse biological activities. Their pharmacological activity makes them desirable as sedative, anxiolytic, hypnotic, anticonvulsant, antitumor, antiviral, antiparasitic or antimicrobial drug candidates. The growing potential inherent in them encourages many researchers to address the challenges of the synthesis of natural products containing complex β-carboline frameworks. In this review, we describe the recent developments in the synthesis of β-carboline alkaloids and closely related derivatives through selected examples from the last 5 years. The focus is on the key steps with improved procedures and synthetic approaches. Furthermore the pharmacological potential of the alkaloids is also highlighted.

Keywords: bioactive molecules; natural products; total synthesis; β-carboline.

Figure 1

Structure of carboline skeleton and drugs containing a β-carboline framework.

Scheme 1

One-pot synthesis of natural product norharman (1) and further β-carboline derivatives.

Scheme 2

Enantioselective synthesis of (S)-eleagnine (2).

Scheme 3

Synthesis of (−)-tetrahydroharman (2), (−)-komaroidine (3), N-(+)-methyltetrahydroharman (4), (+)-1-ethyl-9-methyltetrahydro-β-carboline (5) and (+)-N-acetylkomaroidine (6).

Scheme 4

Synthesis of stolonine C (7).

Scheme 5

Kamal’s improved synthesis of eudistomins I (8), N (9), T (10) and U (11).

Scheme 6

Kamal’s synthesis of eudistomins U (10) and I (8).

Scheme 7

Synthesis of eudistomin U (10).

Scheme 8

Ábrányi-Balogh’s synthesis of isoeudistomin U (12).

Scheme 9

Synthesis of harmalan (13), isoeudistomin M (14), norharman (1), harman (15), eudistomin U (10) and kumujian C (16) via iodine-mediated dehydrogenation.

Scheme 10

Total synthesis of trigonostemines A (17), B (18) and G (19) and a novel synthetic route for the preparation of pityriacitrin (20) and hyrtiosulawesine (21).

Scheme 11

Synthesis of alangiobussine (22) and alangiobussinine (23).

Scheme 12

Synthesis of haploscleridamine (24).

Scheme 13

Synthesis of (±)-peharmaline A (25).

Scheme 14

Pd-catalyzed cross-annulation of phenols (170) and tryptamines (118).

Scheme 15

Synthesis of alkaloids marinacarboline A–D (27–30).

Scheme 16

Total synthesis of metatacarbolines A, C, D, E and F (31–35).

Scheme 17

Synthesis of 6-hydroxymetatacarboline D (36).

Scheme 18

Total synthesis of shishijimicin A (37)—Part 1: Synthesis of β-carboline framework 191.

Scheme 19

Total synthesis of shishijimicin A (37)—Part 2: Synthesis of disaccharide aldehyde 198.

Scheme 20

Total synthesis of shishijimicin A (31)—Part 3: Synthesis of enediyne thioacetate precursor 212.

Scheme 21

Total synthesis of shishijimicin A (37).

Scheme 22

Synthesis of canthine (32) and harmicine (33) via reductive Pictet–Spengler cyclization.

Scheme 23

Synthesis of (−)-harmicine ((−)-39).

Scheme 24

Synthesis of (−)-harmicine ((−)-39).

Scheme 25

One-step synthesis of racemic harmicine (39).

Scheme 26

Five-step synthesis of cordatanine (40).

Scheme 27

Alternate synthesis of cordatanine (40).

Scheme 28

Total synthesis of griseofamine A (41).

Scheme 29

Total synthesis of (+)-deplancheine (42).

Scheme 30

Synthesis of (−)-geissoschizol (43).

Scheme 31

Synthesis of chaetoglines E (44) and F (45).

Scheme 32

First synthesis of 6-oxofascaplysin (46) and a new synthetic route for the preparation of fascaplysin (47).

Scheme 33

One-step synthesis of evodiamine (48).

Scheme 34

Synthesis of norsuaveoline (49), suaveoline (50) and macrophylline (51).

Scheme 35

Synthesis of (S)-(−)-decarbomethoxy-dihydrogambirtannine (52) and formal synthesis of (+)-strictamine (53).

Scheme 36

Formal total synthesis of (±)-strictamine (53).

Scheme 37

Synthesis of (±)-arbornamine (54).

Scheme 38

Synthesis of (+)-tacamonine (55).

Scheme 39

Total synthesis of (−)-17-nor-excelisidine (56) and (+)-geissoschizine (57) by applying direct oxidative cyclization.

Scheme 40

Synthesis of (+)-16-epi-pleiocarpamine (58).

Scheme 41

Synthesis of (+)-16-epi-pleiocarpamine (58), (+)-taberdivarine H (59) and (+)-16-hydroxymethyl-pleiocarpamine (60).

Scheme 42

Total synthesis of C-mavacurine-type alkaloids (61–63).

Scheme 43

Synthesis of eburnane alkaloids (64–67).

Scheme 44

Synthesis of (+)-vallesamidine (68) and (+)-14,15-dehydrostrempeliopine (69) via key intermediate 359.

Scheme 45

First total synthesis of (+)-peganumine A (70).

Scheme 46

Synthesis of reserpine (71).

Scheme 47

Total synthesis of (−)-5-carboxystrictosidine (72).

Scheme 48

Total synthesis of (−)-rubenine (73).